Project Summary Cognitive control appears to be one of the most consistently and severely affected functions in opioid use disorder (OUD), putting opioid users at higher risk of treatment dropout and drug relapse. While treatment programs for OUD typically focus on the cessation of substance use, there is now a firm basis for treatment programs to consider cognitive control difficulties in order to provide more neurocognitive targeted support for people seeking treatment for OUD. Our long-term goal is to improve cognitive control functioning in OUD with the aim to increase opioid users' success in treatment and maintaining abstinence, as well as achieving broader life changes. The main scientific premise is that cognitive control functioning may be improved in OUD by modulating the activity of the anterior cingulate cortex (ACC) with a non-invasive brain stimulation method called robot-assisted transcranial magnetic stimulation (TMS). This premise has been formulated on the basis of strong empirical and theoretical support, as well as recent findings produced by the applicant. Foremost, the ACC is a brain area centrally concerned with cognitive control and implicated in a variety of psychiatric disorders, including substance use disorders. In humans, the reward processing function of the ACC can be investigated using an event-related brain potential called the reward positivity, and numerous reward positivity studies have demonstrated that substance abusers, regardless of drug type, exhibit abnormal ACC activity to rewards. Importantly, TMS delivered to the left dorsal lateral prefrontal cortex has been shown to enhance neuronal activity in the ACC. We recently demonstrated that TMS can modulate the amplitude of the reward positivity in abstinent smokers, bolstering the utility of TMS as a tool to treat substance use disorders. Building on this empirical support, the overall objective in this application is to examine and improve cognitive control functioning in OUD. The rationale for the proposed research is that combining EEG with TMS provides an unprecedented opportunity for the systematic examination of the ACC reward function in OUD, and the potential role of TMS in modulating the level of reward value assigned by the ACC to goal-directed behaviors in OUD. This hypothesis will be tested by pursuing two specific aims. Because the reward positivity has not yet been investigated in an OUD population, our first aim is to use the reward positivity as a means to evaluate the reward function of the ACC in opioid users. Our second aim is to modulate the ACC reward function through the frontal-cingulate circuit via TMS to enhance the reward response by ACC in OUD, as evaluated by reward positivity. The approach is innovative because it would highlight an important yet under-investigated role of ACC dysfunction in OUD, and adapt an existing TMS technique to provide a novel treatment for OUD. Given that the US is in the midst of an OUD epidemic, the empirical findings obtained here would underscore such a need for continued research of the utility of TMS in the understanding and treatment of this disorder.